Method for the Preparation of (S)-N-Methyl-3-(1-Naphthyloxy)-3-(2-Thienyl)Propylamine Hydrochloride (Duloxetine)

ABSTRACT

A method of preparation of (S)—N-methyl-3-(1-naphthyloxy)-3-(2-mienyl)propylamine of Formula (I) and its pharmaceutically acceptable salts, comprising a) reaction of (RS)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine with optically active D-tartaric acid or an acid salt derived from D-tartaric acid forming a mixture of diastereoisomeric salts of N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine and D-tartaric acid (2:1), b) isolation of the salt (S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate (2:1) from the mixture of diastereoisomeric salts in an organic solvent, water or a mixture thereof and release of (S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine by action of an inorganic or organic base, c) demethylation of (S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine by action of an alkylchloroformate of formula ClCOOR (R=C 1 -C 5  alkyl, or C 6 -C 12  aryl or alkylraryl), especially phenyl, ethyl or methyl chloroformate, and d) hydrolytic release of the duloxetine base of formula I and optionally conversion of the base to a salt with the respective acid, or salt of a weak base.

TECHNICAL FIELD

The invention concerns a new method of preparation of(S)—N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula I

known under the generic name duloxetine, and its pharmaceuticallyacceptable salts.

BACKGROUND ART

Duloxetine is a selective serotonin and noradrenaline reuptakeinhibitor, therapeutically useful to treat for example depression andurinary incontinence.

Preparation of Duloxetine and its Intermediate Products is Described forExample in patents EP 0 273 658, U.S. Pat. No. 5,362,886, WO2004/005239, US 2003/0225153. The basic used reaction is described inthe following scheme 1.

Most of the syntheses uses for the reaction already optically activeintermediate product of formula II, i.e.(S)—N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine. In case ofsyntheses of many optically active substances, resolution or obtainingoptically pure intermediates leads to better yields than resolving thefinal products. However, in case of duloxetine, it has turned out thatwhen it is further treated according to Scheme 1 racemization takesplace again. The final product obtained in this way is not, therefore,enantiomerically pure and it is necessary to recrystallize it again. Ofcourse, this decreases the yield of the process.

A solution of undesirable racemization in the course of reactionaccording to Scheme 1 is offered by patent application WO 2004/056795A1. The authors have chosen a method of preparation of racemicduloxetine and its resolving with a suitable chiral acid. Using thismethod, they, of course, prevent possible racemization; however, on theother hand, by also processing the undesirable (R)-enantiomer until thefinal stage they increase losses. In this application,di-p-toluoyltartaric acid is presented as the most suitable acid; inpatent application WO 2005/108386 A1, use of one equivalent of thisderivative of tartaric acid in resolving racemic duloxetine, i.e. 130 gfor 100 g of the base, is mentioned in the Examples.

In the original patents, the reaction according to Scheme 1 was used ascatalysts. These bases are relatively costly and when they are used itis necessary to avoid moisture, with which they can react violently.

Application WO 2004/056795 also publishes a method of performingreaction according to Scheme 1, where the use of a phase transfercatalyst allows for the reaction to proceed also with weaker bases suchas alkali metal hydroxides.

According to our earlier invention (CZ patent 297560, WO 2006/045255) itis advantageous to use, for preparation of(S)—N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (duloxetine),the optically inactive(RS)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formulaIII

which is resolved using an optically active acid, preferably D-tartaricacid. The optically active acid is used in the stoichiometric ratio withrespect to the substance of formula III. The (S)-enantiomer, is isolatedwhich is further demethylated using alkylchloroformates, whereuponhydrolysis is performed and the substance of formula I is isolated.

Preparation of the duloxetine salt is described in Example 2 (Method 2)of U.S. Pat. No. 5,362,886. The final product is obtained via reactionof concentrated hydrochloric acid with a solution of the duloxetine basein ethylacetate. An inoculating crystal of duloxetine hydrochloride isadded to the acidified reaction mixture and the mixture is diluted witha further amount of ethylacetate; after 30 minutes of stirring, themixture is re-concentrated to the initial volume and then stirred atambient temperature for 1 hour and at the temperature 0° C. for 1 hour.However, when this procedure was reproduced it has turned out that theresulting duloxetine hydrochloride was not completely colorless butslightly pinkish to brownish, which can result in an impure product. Theduloxetine molecule is relatively instable, especially in acidicenvironment. Considering that duloxetine hydrochloride is usuallyprepared via neutralization of the base with hydrochloric acid, thecrude product can contain various impurities. The method of the finalpurification is, therefore, very important for obtaining the desiredquality of the substance and the desired yield as well.

The present invention provides a complete and very advantageous solutionof the preparation of duloxetine.

DISCLOSURE OF INVENTION

The invention concerns a new method of preparing(S)—N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula I

and its pharmaceutically acceptable salts, such as for examplehydrochloride, which comprises resolving of(RS)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formulaIII,

first by converting it to a mixture of diastereoisomeric salts ofN,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate viareaction with optically active tartaric acid in the molar ratio 1:2relative to the substance of formula III or with optically active alkalimetal tartrate or ammonium tartrate, or an alkylammonium tartrate, offormula IV, in the molar ratio 1:1, followed by isolating the salt(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(2:1) (Scheme 2) from the mixture of the diastereoisomeric salts in anorganic solvent, water or a mixture thereof.

(S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula(S)-(III) is then released from the salt(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(2:1) by action of an inorganic or organic base, followed bydemethylation with an alkylchloroformate of formula ClCOOR(R=C₁-C₅alkyl, or C₆-C₁₂ aryl or alkylaryl), and, finally, by hydrolyticallyreleasing the duloxetine base of formula I.

D-tartaric acid in combination with potassium (sodium, lithium)hydroxide, hydroxylamine or the respective alkylamine in an equimolarratio to D-tartaric acid can be used in an equivalent manner instead ofthe tartrate.

The starting substance of formula III is prepared according to Scheme 1via reaction of (RS)—N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylaminewith 1-fluornaphtalene in a solution of dimethylsulfoxide, at 80 to 150°C. in the presence of a base selected from carbonates, hydroxides oralcoholates of alkali metals. This arrangement allows for catalysis witha weaker base without use of phase-transfer catalysts.

An optically active acid is used for resolving(RS)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formulaIII. According to the present invention, preferably 0.5 equivalent ofD-tartaric acid or 1 equivalent of an alkali metal D-tartrate orammonium D-tartrate, or alternatively alkylammonium tartrate of formulaIV can be used. Monopotassium D-tartrate has turned out to beparticularly advantageous. Advantages of the method of preparationaccording to the invention compared with using 1 equivalent ofD-tartaric acid include:

(1) the salt can be easily prepared in an aqueous environment,especially in a mixture of water and a polar aprotic solvent (e.g. DMSO,DMF). According to a preferred embodiment, a polar aprotic solvent, e.g.dimethylsufoxide, is used as the reaction environment already duringpreparation of the compound of formula III, and after performing thereaction, the reaction mixture is only diluted with water (at leastdouble amount (by volume) of water with respect to the polar aproticsolvent), 0.5 equivalent of tartaric acid or 1 equivalent ofmonopotassium tartrate is added, and after cooling, the precipitatedsalt is filtered off, which avoids laborious extraction of the base withan organic solvent,(2) better capacity to crystallize of the desired salt(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(2:1), which leads to easier reproducibility of the resolution and alsoto higher optical purity of the obtained salt,(3) possibility to use easily regenerable monopotassium tartrate or only0.5 equivalent of tartaric acid, which leads to lower expensesconcerning raw materials and also lower amount of waste produced duringpreparation.

Using non-derivatized tartaric acid or its acidic salts is advantageousfor the following reasons: (a) low molecular weight, which results inusing lower amount of relatively expensive chiral agent (one needs, for1 mole of base III, e.g., 75 g of tartaric acid (0.5 equivalent) or 188g of monopotassium tartrate (1 equivalent) or 424 g ofdi-p-toluoyltartaric acid (1 equivalent)); (b) easy regeneration in theform of directly usable acid tartrate (during regeneration from aqueousliquors, after addition of 1 equivalent of a mineral acid, a very badlywater-soluble acid tartrate (e.g. of monopotassium tartrate)crystallizes), In contrast, derivatives of tartaric acid based onesters, e.g. di-p-toluoyltartaric acid, are usually instable in a basicaqueous environment (possibility of hydrolysis); in addition, duringregeneration from aqueous liquors it is usually necessary, afteracidification, to make extraction with an organic solvent andcrystallization.

The salt(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(2:1) is isolated from the mixture of diastereoisomeric salts from asolvent from the group of aliphatic or cyclic ethers, e.g.tetrahydrofuran or diethylether, C₃-C₆ ketones, e.g. acetone, or loweralcohols, e.g. C₁-C₃ ones, or water, or a mixture of these solvents inan appropriate ratio, at temperatures from 0 to 80° C. An aqueoussolution of THF containing from 0 up to 10% of water is preferably used.

(S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula(S)-(III) is released from the salt(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(2:1) by action of an inorganic or organic base in the environment ofwater and a water-immiscible organic solvent.

The prepared (S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine(S)-(III) is demethylated in the next step. Demethylation is performedby action of an alkyl or aryl chloroformate from the group of compoundsfor general formula ClCOOR, wherein R is selected from the group ofC₁-C₅ alkyls or C₆-C₁₂ aryls or alkylaryls, in a solvent mixture oftoluene and diisopropylethylamine at temperatures from 50 to 110° C.,followed by hydrolysis with an alkali metal hydroxide.

The undesired(R)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine can bereturned to production process after it is racemized with an inorganicor organic base, e.g. potassium tert-butanolate, in an organic solventenvironment, preferably in dimethylsulfoxide. After completion of thereaction, the mixture is diluted with water and enters to the process asa recycled portion along with the original raw material before resolvingof racemic (RS)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamineof formula III into individual diastereoisomers.

The duloxetine base can be converted to any pharmaceutically acceptablesalt. The hydrochloride and oxalate have been previously described,while the hydrochloride is commonly used for medical purposes.

A method of preparation of the hydrochloride salt from the duloxetinebase represents another aspect of the present invention. Preparation ofthis salt is commonly performed via reaction of the duloxetine base withconcentrated hydrochloric acid in ethylacetate environment. However, ithas now turned out that substitution of ethylacetate by a lower ketone,such as for example ethylmethylketone, results in higher yields ofhigher quality duloxetine hydrochloride, especially when duloxetinehydrochloride is prepared and isolated via the method according to thisinvention. For comparison of effects of the used solvent on quality ofthe substance, we have used contaminated duloxetine hydrochloride thatwas obtained as the second fraction from mother liquors after theirconcentration. In Table 1, a HPLC print-out (C18 reverse column, mobilephase: water/acetonitrile, phosphate buffer pH 7.6) is presented showinganalysis of the starting substance and then of the purified substanceobtained after 1 hour refluxing in a six-fold amount of the solvent(i.e. 6 ml of the solvent for 1 g of the starting substance), cooling toambient temperature, filtration and drying.

TABLE 1 Effect of used solvent on quality of the substance StartingSubstance purified in Substance purified in Impurity substanceethylacetate ethylmethylketone RRT 0.28 0.26 % 0.16 % 0.09 % RRT 0.530.54 % 0.42 % 0.38 % RRT 0.88 0.42 % 0.12 % <0.05 %   RRT 1.05 0.40 %0.36 % 0.30 % RRT 1.27 0.44 % 0.19 % 0.11 % RRT 1.68 0.15 % 0.09 % <0.05%   RRT 2.24 0.08 % <0.05 %   <0.05 %   RRT 2.29 0.07 % <0.05 %   <0.05%   RRT 3.17 0.61 % 0.30 % <0.05 %   Sum of 2.97 % 1.64 % 0.88 %impurities

It is apparent from the Table that the content of all impurities islower in the case when a ketone, in this case ethylmethylketone, wasused. It is, therefore, apparent that ketones are more suitable solventsfor preparation of duloxetine hydrochloride than esters, such as forexample ethylacetate, both during its preparation via neutralization ofthe base with hydrochloric acid and for its possible purification.

It can be expected that ketones will be more suitable solvents thanesters also for preparation of other pharmaceutically acceptable saltsof duloxetine such as for example hydrobromide and hydrogensulfate.

The invention is further illustrated in the following examples.

EXAMPLES Example 1(RS)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate

A mixture of N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine (185 g, 1mole), potassium hydroxide (112 g, 2 moles) and 1-fluoronaphthalene (146g, 1 mole) in dimethylsulfoxide (1000 ml) is stirred at 110° C. for 2hours. After cooling down to 20° C., the mixture is filtered, dilutedwith water (3 l), monopotassium D-tartrate (188 g, 1 mole) is added, andthe mixture is stirred at 80° C. for 0.5 hour. After cooling down, theprecipitated product is sucked off, washed with water and dried. Yield:328 g (85%).

Example 2(RS)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate

A mixture of N,N-dimethyl-3-hydroxy-3-(2-thienyl)propylamine (185 g, 1mole), potassium hydroxide (112 g, 2 moles) and 1-fluoronaphthalene (146g, 1 mole) in dimethylsulfoxide (1000 ml) is stirred at 110° C. for 2hours. After cooling down to 20° C., the mixture is filtered, dilutedwith water (3 l), D-tartaric acid (75 g, 0.5 mole) is added and themixture is stirred at 80° C. for 0.5 hour. After cooling down, theprecipitated product is sucked off, washed with water and dried. Yield:313 g (81%).

Example 3(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate

(RS)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(773 g, 1 mole) is dissolved in warm tetrahydrofuran (1500 ml) withaddition of water (40 ml). After cooling down to ambient temperature,the mixture is stirred for 24 h. The precipitated crystals arerecrystallized once more in tetrahydrofuran (400 ml) with an addition ofwater (12 ml) following the same procedure. Yield: 170 g (22%). Opticalpurity: 99.5% ee (CE).

Example 4(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate

(RS)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(773 g, 1 mole) is dissolved in THF (1500 ml) with an addition of water(40 ml) under reflux. After gradual cooling down to ambient temperature,diethylether (300 ml) is added drop-wise to the mixture over 6 hours.The precipitated crystals are sucked off and washed with THF. Yield: 232g (30%). Optical purity: 93% ee (CE).

Example 5 (S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylaminehydrochloride (duloxetine)

Diisopropylethylamine (210 ml) is added to a solution of(S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)-propanamine (311 g;99.6% ee) in toluene (1200 ml) and phenylchloroformate (150 ml) is thenadded at 60° C. After two hours of stirring at 80° C., the mixture iscooled down, shaken with a diluted solution of hydrochloric acid, waterand a 2% solution of sodium hydrogencarbonate. The organic phase isdried with sodium sulfate and evaporated. The evaporation residue isdissolved in ethanol (300 ml) and a 5M solution of potassium hydroxide(400 ml) is added drop-wise under reflux. After two hours of refluxing,the mixture is evaporated to half the volume, diluted with water (1000ml) and extracted with toluene (300 ml). The organic phase is dried withsodium sulfate and evaporated. The evaporation residue is dissolved inethylmethylketone (300 ml) and concentrated HCl (1 mole), diluted withethylmethylketone (300 ml), is added drop-wise at 0° C.; then themixture is stirred for two hours. The precipitated crystals are thensucked off. Yield: 250 g (75%), m.p.: 167-169° C. Recrystallization fromethylmethylketone affords colorless crystalline duloxetinehydrochloride, m.p. 170.5-171.5° C. Optical purity: 99.9% ee (CE),chemical purity: 99.9% (HPLC).

1. A method of preparation of(S)—N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula I

and its pharmaceutically acceptable salts, comprising a) reaction of(RS)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formulaIII

with optically active D-tartaric acid or an acid salt derived fromD-tartaric acid forming a mixture of diastereoisomeric salts ofN,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine and D-tartaricacid (2:1), b) isolation of the salt(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(2:1) from the mixture of diastereoisomeric salts in an organic solvent,water or a mixture thereof and release of(S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine of formula(S)-(III) by action of an inorganic or organic base

c) demethylation of(S)—N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine by action ofan alkylchloroformate of formula ClCOOR(R=C₁-C₅ alkyl, or C₆-C₁₂ aryl oralkylaryl), especially phenyl, ethyl or methyl chloroformate, and d)hydrolytic release of the duloxetine base of formula I and optionallyconversion of the base to a salt with the respective acid, or salt of aweak base, characterized in that one uses, as the optically activesubstance in step (a), D-tartaric acid in the molar ratio 1:2 relativeto the substance of formula III, or an alkali metal acid D-tartrate orammonium tartrate, or alternatively alkylammonium tartrate of formula IV

in the molar ratio 1:1 relative to the substance of formula III.
 2. Themethod according to claim 1, characterized in that the reaction in stepa) is performed in the presence of water.
 3. The method according toclaim 2, characterized in that the reaction is performed in a solventmixture composed of water and a polar aprotic solvent in a 2-fold to10-fold (by volume) excess of water relative to the polar aproticsolvent.
 4. The method according to claim 3, characterized in thatdimethylsulfoxide is used as the polar aprotic solvent.
 5. The methodaccording to claim 1, characterized in that one uses, in step (b), forisolation of the salt(S)—N,N-dimethyl-3-(naphthyloxy)-3-(2-thienyl)propylamine/D-tartrate(2:1) from the mixture of diastereoisomeric salts, a solvent selectedfrom the group of aliphatic and cyclic ethers, C₃-C₆ ketones, C₁-C₃alcohols and water, or a mixture thereof, and a temperature of from 0 to80° C.
 6. The method according to claim 5, characterized in that anaqueous solution of THF containing from 0 to 10% of water is used as thesolvent.
 7. The method according to claim 1, characterized in that, instep (d), the substance of formula I is converted to its hydrochloridevia reaction with hydrochloric acid in an environment of the solventethylmethylketone and the obtained duloxetine hydrochloride iscrystallized from said solvent.